Endogenous glucose production (EGP) is a critical process that maintains blood glucose levels under fasting conditions. While EGP is suppressed by both glucose and insulin, it is inappropriately elevated in T2DM and is the major source of hyperglycemia in these individuals. Although rises in plasma glucose and insulin rapidly inhibit EGP in nondiabetic individuals, T2DM is associated with loss of these suppressive effects of glucose and insulin on EGP. Of note, recent rodent studies suggest that hepatic glucose fluxes are centrally regulated, since activation of central KATP channels by insulin and glucose suppresses EGP and gluconeogenesis. It will be important to establish how important this is to normal regulation of glucose homeostasis in humans, and whether this central regulation is impaired in individuals with T2DM. We plan to address these questions in human subjects, using state-of-the-art 'pancreatic clamp' studies with quantification of hepatic glucose fluxes by tracer methodologies and magnetic resonance spectroscopy (MRS). We will first determine whether and how activation of KATP channels impacts hepatic glucose fluxes in nondiabetic subjects under fixed hormonal conditions, and whether this effect can be abolished by inhibiting KATP channels. Additionally, we will determine the extent to which central pathways of glucose regulation could contribute to the suppressive effects of glucose and insulin on EGP. We will then examine whether this central regulation is impaired in T2DM. Since our preliminary data suggest that central inputs play a key role in the regulation of hepatic glucose fluxes in humans, restoring this regulation could be an important target for intervention in individuals with T2DM.